Disproportionate hyperproinsulinemia, Β-cell restricted prohormone convertase 2 deficiency, and cell cycle inhibitors Expression by human islets transplanted into athymic nude mice: Insights into nonimmune-mediated mechanisms of delayed islet graft failure

Alberto M. Davalli, Lucia Perego, Federico Bertuzzi, Giovanna Finzi, Stefano La Rosa, Adam Blau, Claudia Placidi, Rita Nano, Luisa Gregorini, Carla Perego, Carlo Capella, Franco Folli

Research output: Contribution to journalArticle

20 Citations (Scopus)

Abstract

To leam more about nonimmune-mediated islet graft failure, we transplanted different preparations (preps) of isolated human islets under the kidney capsule of streptozotocin (STZ)-diabetic nude mice. One month after the implantation of 1,000 or 2,000 islets, grafts were harvested for morphological, immunohistochemi-cal, and ultrastructural analysis. Only a single islet prep cured the diabetes out of all the recipients, while the remaining preps showed only partial function after the implantation of 2,000 islets. Transplanted mice showed high circulating proinsulin levels but, with the exclusion of those bearing curative grafts, relatively low mature insulin levels. Engrafted β-cells showed positive carboxypeptidase E (CPE) and prohormone convertase 1 (PCI) staining, while prohormone convertase 2 (PC2) was undetectable. In contrast, PC2 was abundantly expressed by engrafted a-cells. Moreover, engrafted β-cells did not show evidence of replication, and preapoptotic β-cells, with intra- and extracellular amyloid deposition, were detected with electron microscopy. Cell cycle inhibitors pl6 INK4, p21 WAF1, and p27 Kipl were abundantly expressed in the islet grafts and showed a predominant nuclear localization. In conclusion, diabetic nude mice transplanted with human islets showed disproportionate hyperproinsulinemia and graft evidence of β-cell restricted PC2 depletion, amyloid deposition and β-cell death, and lack of β-cell replication with nuclear translocation of p27 Kipl and p21 WAF1 that together may contribute to delayed graft failure.

Original languageEnglish
Pages (from-to)1323-1336
Number of pages14
JournalCell Transplantation
Volume17
Issue number12
DOIs
Publication statusPublished - 2008

Fingerprint

Proprotein Convertase 2
Nude Mice
Grafts
Cell Cycle
Cells
Transplants
Amyloid
Proprotein Convertase 1
Carboxypeptidase H
Bearings (structural)
Proinsulin
Insulin
Cell death
Streptozocin
Medical problems
Electron microscopy
Capsules
Hyperproinsulinemia
Electron Microscopy
Cell Death

Keywords

  • Athymic nude mice
  • Islet transplantation
  • p27
  • pl6 ; p21
  • Prohormone convertase 2 (PC2)
  • Proinsulin processing

ASJC Scopus subject areas

  • Cell Biology
  • Transplantation
  • Biomedical Engineering

Cite this

Disproportionate hyperproinsulinemia, Β-cell restricted prohormone convertase 2 deficiency, and cell cycle inhibitors Expression by human islets transplanted into athymic nude mice : Insights into nonimmune-mediated mechanisms of delayed islet graft failure. / Davalli, Alberto M.; Perego, Lucia; Bertuzzi, Federico; Finzi, Giovanna; La Rosa, Stefano; Blau, Adam; Placidi, Claudia; Nano, Rita; Gregorini, Luisa; Perego, Carla; Capella, Carlo; Folli, Franco.

In: Cell Transplantation, Vol. 17, No. 12, 2008, p. 1323-1336.

Research output: Contribution to journalArticle

Davalli, Alberto M. ; Perego, Lucia ; Bertuzzi, Federico ; Finzi, Giovanna ; La Rosa, Stefano ; Blau, Adam ; Placidi, Claudia ; Nano, Rita ; Gregorini, Luisa ; Perego, Carla ; Capella, Carlo ; Folli, Franco. / Disproportionate hyperproinsulinemia, Β-cell restricted prohormone convertase 2 deficiency, and cell cycle inhibitors Expression by human islets transplanted into athymic nude mice : Insights into nonimmune-mediated mechanisms of delayed islet graft failure. In: Cell Transplantation. 2008 ; Vol. 17, No. 12. pp. 1323-1336.
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abstract = "To leam more about nonimmune-mediated islet graft failure, we transplanted different preparations (preps) of isolated human islets under the kidney capsule of streptozotocin (STZ)-diabetic nude mice. One month after the implantation of 1,000 or 2,000 islets, grafts were harvested for morphological, immunohistochemi-cal, and ultrastructural analysis. Only a single islet prep cured the diabetes out of all the recipients, while the remaining preps showed only partial function after the implantation of 2,000 islets. Transplanted mice showed high circulating proinsulin levels but, with the exclusion of those bearing curative grafts, relatively low mature insulin levels. Engrafted β-cells showed positive carboxypeptidase E (CPE) and prohormone convertase 1 (PCI) staining, while prohormone convertase 2 (PC2) was undetectable. In contrast, PC2 was abundantly expressed by engrafted a-cells. Moreover, engrafted β-cells did not show evidence of replication, and preapoptotic β-cells, with intra- and extracellular amyloid deposition, were detected with electron microscopy. Cell cycle inhibitors pl6 INK4, p21 WAF1, and p27 Kipl were abundantly expressed in the islet grafts and showed a predominant nuclear localization. In conclusion, diabetic nude mice transplanted with human islets showed disproportionate hyperproinsulinemia and graft evidence of β-cell restricted PC2 depletion, amyloid deposition and β-cell death, and lack of β-cell replication with nuclear translocation of p27 Kipl and p21 WAF1 that together may contribute to delayed graft failure.",
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AU - Davalli, Alberto M.

AU - Perego, Lucia

AU - Bertuzzi, Federico

AU - Finzi, Giovanna

AU - La Rosa, Stefano

AU - Blau, Adam

AU - Placidi, Claudia

AU - Nano, Rita

AU - Gregorini, Luisa

AU - Perego, Carla

AU - Capella, Carlo

AU - Folli, Franco

PY - 2008

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N2 - To leam more about nonimmune-mediated islet graft failure, we transplanted different preparations (preps) of isolated human islets under the kidney capsule of streptozotocin (STZ)-diabetic nude mice. One month after the implantation of 1,000 or 2,000 islets, grafts were harvested for morphological, immunohistochemi-cal, and ultrastructural analysis. Only a single islet prep cured the diabetes out of all the recipients, while the remaining preps showed only partial function after the implantation of 2,000 islets. Transplanted mice showed high circulating proinsulin levels but, with the exclusion of those bearing curative grafts, relatively low mature insulin levels. Engrafted β-cells showed positive carboxypeptidase E (CPE) and prohormone convertase 1 (PCI) staining, while prohormone convertase 2 (PC2) was undetectable. In contrast, PC2 was abundantly expressed by engrafted a-cells. Moreover, engrafted β-cells did not show evidence of replication, and preapoptotic β-cells, with intra- and extracellular amyloid deposition, were detected with electron microscopy. Cell cycle inhibitors pl6 INK4, p21 WAF1, and p27 Kipl were abundantly expressed in the islet grafts and showed a predominant nuclear localization. In conclusion, diabetic nude mice transplanted with human islets showed disproportionate hyperproinsulinemia and graft evidence of β-cell restricted PC2 depletion, amyloid deposition and β-cell death, and lack of β-cell replication with nuclear translocation of p27 Kipl and p21 WAF1 that together may contribute to delayed graft failure.

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KW - pl6 ; p21

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